Pyrrolizidine alkaloids are widely distributed in the nature, existing in about 3% of flowering plants. More than 660 pyrrolizidine alkaloids have been identified from over 6000 plants in three families, Boraginaceae, Compositae, and Legumionsae. Most of the naturally occurring pyrrolizidine alkaloids are known to be hepatotoxic and tumorigenic in animals and humans. Pyrrolizidine alkaloids are generally divided into three types based on the necine bases: retronecine (including its 7-α enantiomer), otonecine, and platynecine, as shown in FIG. 1. The former two types contain unsaturated necine bases and are highly hepatotoxic and genotoxic, while the last type with a saturated necine base are generally thought to be less or non-toxic.
The pyrrolizidine alkaloid-containing plant is likely to be the most common poisonous plants that affect livestock, wildlife, and humans, among which horses, cattle, sheep, goats, swine, chickens, quails, and doves are most susceptible animal species. Acute poisoning causes massive hepatotoxicity with hemorrhagic necrosis. Chronic poisoning takes place mainly in liver, lungs, and blood vessels, and in some instances kidneys, pancreas, gastrointestinal tract, bone marrow, and brain. Prolonged exposures may cause cell enlargement (megalocytosis), veno-occlusion in liver and lungs, fatty degeneration, nuclei enlargement with increasing nuclear chromatin, loss of metabolic function, inhibition of mitosis, proliferation of biliary tract epithelium, liver cirrhosis, nodular hyperplasia, and adenomas or carcinomas.
The earliest case of pyrrolizidine alkaloids-induced intoxication in human was reported in 1920 and associated with the ingestion of pyrrolizidine alkaloid-containing herbal tea. Since then, more than 8000 pyrrolizidine alkaloid-poisoning cases have been documented in many countries, including Afghanistan, Britain, China, Germany, Hong Kong, India, Jamaica, South Africa, Switzerland, and the United States. The most serious known disaster of human pyrrolizidine alkaloid poisoning occurred in 1975 in Northwest Afghanistan, and was associated with the consumption of bread made from wheat flour contaminated with pyrrolizidine alkaloids. Examination of 7200 inhabitants from the affected villages showed evidence of liver disease in 22.6% of those examined. Consumption of pyrrolizidine alkaloid-containing herbs, which may be misused as medicines, or pyrrolizidine alkaloid-contaminated food stuffs, are among the common causes for pyrrolizidine alkaloid-induced intoxication.
Ingestion of pyrrolizidine alkaloids may lead to hepatic sinusoidal obstruction syndrome (HSOS), a clinical syndrome characterized by hepatomegaly, ascites and hyperbilirubinaemia due to sinusoidal congestion caused by pyrrolizidine alkaloids ingestion, haematopoietic stem cell transplantation or solid organ transplantation. The clinical diagnosis of HSOS is largely based on the classical triad of weight gain, painful hepatomegaly and jaundice, however, none of them is specific. The diagnosis of HSOS induced by pyrrolizidine alkaloid-containing herbs was all based on clinical symptoms and on the history of drug/herb exposure reviewed retrospectively. Therefore, a causative diagnosis of HSOS cannot be established because the detailed information on the intake of herbs is unavailable in most of the cases where multi-herb preparations were used. It is known in the art that pyrrolizidine alkaloids themselves are non-toxic, and exert their toxicity by metabolic activation to form the electrophile “pyrrolic” metabolites, which could rapidly react with cellular macromolecules such as protein and DNA (see FIG. 2). The intervention between “pyrrolic” metabolites and macromolecules can be via linkage of either —N— or —S— in different amino acids to form pyrrole-protein and pyrrole-DNA adducts. However, there is no known method for the clinical diagnosis or laboratory determination of pyrrolizidine alkaloid-induced intoxication.